TheoriginaltheoryofferedbyBraak&Braak(1991)?thatneurofibrillarytanglepathologyproceedsalongwell- definedpredilectionsitesbeginninginthemedialtemporalcortex?hasbeenmodifiedbythesameauthorto suggest that the pathologic process instead commences in the lower brainstem (Braak et al 2011). The first visiblepathologicchangesarenowthoughttooccurinthelocuscoeruleus(LC)andthenspreadviaitsaxonal projections to transentorhinal/entorhinal cortex (TEC). We propose to study LC change using a novel computational morphology method, combined with novel methods of measuring white matter microstructural tractography and functional connectivity to TEC. These new methods are designed to overcome major shortcomingsincurrentneuro-MRIanalysismethodsthatlimittheabilitytodetectsubtlestructuralandfunctional changesassociatedwithearlyAD.Suchalterationsacrosstheaging-MCI-ADcontinuum,aswellasinthose cognitivelynormalindividualswithriskfactorsforAD(e.g.,CSFADbiomarkers;?apolipoproteinEe?4carriers), would provide significant advances in our understanding of the pathogenesis of AD across clinical transition pointsandperhapsduringthis?silent?period(i.e.,priortotheoccurrenceoftraditionalADbiomarkerpositivities). UsingournewlydevelopeddiagnosticandMRImetrics,weproposetoquantifyvariationsinLCmorphologyand itsprojectionstoTEC(whichwetermtheLC-TECsystem). Aim 1. Examine locus coeruleus morphology, contrast, and associated cortical thickness. Morphological variationswillbecharacterizedbysphericalwavedecomposition(SWD)ofhigh-resolutionanatomicalMRIdata supplementedbyrecentcontrastratio(Takahashietal.2015)analysesofT1FastSpinEchoMRIscans. Aim2.ExaminestructuralconnectivityoftheLC-TECsystem.Neuralconnectivitywillbecharacterizedbyour noveldiffusiontensorimaging(DTI)tractographymethod(geometric-opticbasedentropyspectrumpathways, GO-ESPDTI)toquantifyafferentandefferentpathwaysbetweentheLCandTEC,andefferentprojectionsfrom theLCtocerebellumandcortex. Aim3.ExaminefunctionalconnectivityoftheLC-TECsystem.Restingstatefunctionalmodesandconnectivity willbederivedfromournovelentropyfielddecomposition(EFD)analysisofrsFMRIdataguidedbytheprediction thatADtauopathyinitsearliestphasesisnotdeterminedbylargelossesofneuronsbutbyenormousnumbers of nerve cells that survive with limited functionality (Braak & Del Tredici 2015);? alterations in functional connectivityoftheLC-TECsystemwillserveasasurrogatemarkerofthislimitedfunctionality. Demonstrations of improvement in diagnostic and imaging precision in Preclinical AD will have an important impactonprospectivedesignoffuturestudiesand,ifsuccessful,producenewbiomarkerassessmentmodalities andfundamentalshiftsinourtherapeutictargetsforAD.